ISCHEMIC HEART DISEASE

LEARNING OBJECTIVES


1. Understand determinants of myocardial supply and demand.

2. Understand the pathophysiology of stable and unstable coronary plaques.

3. Be able to identify several mechanisms by which unstable angina can occur.

4. Understand mechanisms of acute myocardial infarction.

5. Understand pathophysiology of various complications of acute MI, including right ventricular infarction, congestive heart failure, heart block, acute myocardial rupture, acute mitral regurgitation, and cardiogenic shock.

6. Understand mechanisms by which the various ischemic syndromes (stable and unstable angina, and acute MI) can be treated medically and with interventional therapies.

7. Be able to identify the major risk factors for development of coronary artery disease.
 
 
 
ISCHEMIC HEART DISEASE AND ACUTE MYOCARDIAL ISCHEMIA



What is ischemia?

Imbalance between supply and demand resulting in one of many clinical syndromes.
 
SYNDROME DESCRIPTION
Ischemic heart disease Condition in which an imbalance between myocardial oxygen supply and demand results in myocardial hypoxia and accumulation of waste metabolites; most often due to atherosclerotic disease of the coronary arteries ("coronary artery disease")
Angina pectoris Uncomfortable sensation in the chest or neighboring anatomic structures produced by myocardial ischemia
Stable angina Chronic pattern of transient angina pectoris, precipitated by physical activity or emotional upset, relieved by rest within a few minutes; episodes often associated with temporary depression of the ST segment, but permanent myocardial damage does not result
Variant angina Typical anginal discomfort, usually at rest, which develops because of coronary artery spasm, rather than an increase of myocardial oxygen demand; episodes often associated with transient shifts of the ST segment (usually ST elevation)
Unstable angina Pattern of increased frequency and duration of angina episodes, produced by less exertion, or at rest; high frequency of progression to myocardial infarction if untreated
Silent ischemia Asymptomatic episodes of myocardial ischemia; can be detected by EKG and other laboratory techniques
Myocardial infarction (See Chapter 7) Region of myocardial necrosis usually due to prolonged cessation of blood supply; most often results from acute thrombus at site of coronary atherosclerotic stenosis; may be first clinical manifestation of ischemic heart disease, or there may be a history of angina pectoris

 

Determinants of myocardial blood supply and consumption (demand)

Supply:

1. Coronary blood flow

2. Oxygen saturation of blood

3. Hemoglobin content of blood
 
 

Coronary blood flow is proportional to coronary perfusion pressure divided by coronary vascular resistance.

Coronary perfusion pressure is determined primarily by the aortic diastolic pressure and can be reduced abruptly beyond the site of high grade (> 70%) coronary artery stenoses.

Coronary vascular resistance is determined by external compressive forces as well as metabolic, endothelial, and neural factors which regulate intrinsic coronary tone via auto- regulation.

Oxygen saturation of the blood can be reduced by interference with the alveolar-capillary interface, as can occur in many lung diseases. Oxygen saturation could also be reduced by a right-to-left shunt causing admixture of venous and arterial blood.

Hemoglobin content of the blood is reduced in any condition causing anemia.
 
 

Demand:

1. Wall tension (proportional to P x r/2h)

2. Heart rate

3. Myocardial contractility
 
   Myocardial oxygen supply                                                                Myocardial oxygen demand 
Diastolic perfusion pressure
  
Wall Tension
( P x r / 2h )
Coronary vascular resistance
· external compression
· intrinsic regulation
    - local metabolites
    - endothelial factors
    - neural innervation
   Heart rate
02-carrying capacity
Contractility



THE CORONARY ATHEROSCLEROTIC PLAQUE

Perhaps the most common mechanism of coronary ischemia is the development of coronary atherosclerotic plaque resulting in reduced myocardial oxygen supply. Atherosclerotic plaques most likely develop at sites of fatty streaks, in areas where there are accumulations of "foam cells" which are filled with lipid-laden macrophages. Plaques may be either "soft" or "hard", depending on the ratio of lipid-laden foam cells to fibrous tissue within the plaque. Recent research suggests that softer, lipid-laden plaques may be more prone to plaque rupture resulting in unstable angina or acute myocardial infarction. A schematic diagram of "plaque evolution" is presented below.

Risk factors for the development of atherosclerotic plaques include:

1. Hyperlipidemia (In particular, elevated total cholesterol, elevated LDL cholesterol, reduced HDL cholesterol, and elevated LDL/HDL ratio)

2. Cigarette smoking

3. Hypertension

4. Diabetes mellitus

5. Family history of premature coronary artery disease
 

 In general the stable fibrous atherosclerotic plaque will tend to cause either no symptoms or stable angina pectoris, unless other factors occur which change the supply/demand balance. If myocardial demand abruptly increases, the pattern of angina may change. More commonly, the morphology of the coronary plaque is altered, probably due to a complex interaction involving initial damage to endothelial cells, activated macrophages, platelet deposition, and ultimately thrombus formation. Thrombus may be either nonocclusive or occlusive and may lead to myocardial infarction. In addition, smooth muscle cells which become activated and migrate from the arterial media to the intima may result in a proliferative, rapidly progressive coronary atherosclerotic plaque.
 

ACUTE MYOCARDIAL INFARCTION

An abrupt disruption of the coronary artery plaque, leading to occlusive thrombus formation is the most common cause of acute myocardial infarction. This initiates an "ischemic cascade", which progresses as outlined below:

1. Decreased diastolic compliance (diastolic dysfunction)

2. Decreased systolic function (usually localized)

3. Ischemic electrocardiographic changes

4. Clinical symptoms of chest discomfort or other "anginal equivalents"

5. Release of breakdown products due to cell death, i.e. CPK, LDH, troponin-i enzymes.

 Just as there is a time dependent "ischemic cascade" for the clinical manifestations of acute MI, so too there is a pathological time course as noted below:


   TABLE 7.2. Pathologic Timecourse in Transmural Infarction
TIME         EVENT
Early changes
 
1 - 2min ATP levels fall; cessation of contractility
10 min 50% depletion of ATP; cellular edema, decreased membrane potential and susceptibility to arrhythmias
20 - 24 min Irreversible cell injury
1 - 3 hours Wavy myofibers
4 - 12 hours Hemorrhage, edema, PMN infiltration
18 - 24 hours Coagulation necrosis (pyknotic nuclei with eosinophilic
cytoplasm), edema
2-4 days Total coagulation necrosis (no nuclei or striations, rimmed by hyperemic tissue); monocytes appear
Late Changes
 
5 - 7 days Yellow-softening from resorption of dead tissue by macrophages
7 days + Ventricular remodeling
7 weeks Fibrosis and scarring complete

Clinical presentation of acute MI

• Chest discomfort, characteristically described as "pressure" rather than pain or as tightness or heaviness

• Usually located in the center of the chest over an area the size of a fist rather than in a localized point. There is often radiation of discomfort to either or both upper arms or shoulders, sometimes to the neck and into the jaw or into the back. There is often accompanying diaphoresis (sweatiness), shortness of breath, and nausea or vomiting.

• The physical exam may be entirely unremarkable but may demonstrate an S4 gallop, occasionally an S3 gallop if myocardial infarction is large and leads to significant left ventricular dysfunction. Occasionally a dyskinetic apical impulse may be present if an extensive antero-apical MI occurs. A systolic murmur may occur with acute mitral regurgitation or ventricular/septal defect. Jugular venous distention (JVD) may be present in the setting of right ventricular infarct or when there is significant biventricular heart failure. Pulmonary rales may be present if left ventricular failure is present.

• Electrocardiographic changes include ST segment elevation followed ultimately by T-wave inversion and evolution of Q-waves over a time course of 24 to 48 hours.

• The location of the myocardial infarction is dependent on the site of coronary thrombosis as are the potential complications which may follow. Coronary artery anatomy is reviewed below:


 

 With regard to anatomy, please note the following: • Lesions of the left main coronary artery are most critical given that this short trunk ultimately supplies approximately two-thirds of the myocardium.

• Of the three major coronary arteries (left anterior descending, circumflex, and right) the left anterior descending supplies proportionately the most myocardium, perhaps 40% on average. Occlusion of the proximal LAD, therefore, may cause a large area of myocardial necrosis and this may lead to severe left ventricular impairment and congestive heart failure.

Since a large proportion of the intraventricular septum is supplied by the LAD, conduction system structures which course through the septum (the bundle of His and the His-Purkinji system) may be injured. This may result in heart block (LBBB, RBB, Mobitz II A-V block, or complete heart block) which may be irreversible and require permanent pacemaker placement. If the anterior infarct is large and involves the entire apex of the heart, intraventricular thrombus may occur and lead to embolization.

• Occlusion of the right coronary artery usually causes less impairment to left ventricular function. The right ventricle, however, is supplied primarily by the right coronary artery and right ventricular infarction may occur (see P. 9.) The S/A nodal artery is supplied 70% of the time from the right coronary artery and therefore sinus node dysfunction and slowing may occur. The AV nodal artery arises from the posterior descending branch, which is a branch of the right coronary artery in 85% of individuals. Therefore, transient heart block at the level of the A-V node may occur (1st degree, Mobitz I, or 3rd degree A-V block), which is usually reversible and does not require permanent pacemaker implantation. Finally, the posterior descending artery is the primary source of blood to the posterior papillary muscle which may be prone to muscular rupture in the setting of a large inferoposterior MI.
 
 

 Complications of acute myocardial infarction:

    Please refer to Lecture 5: Complications of AMI
 

TREATMENT OF ISCHEMIC HEART DISEASE

The treatment of the patient with ischemic coronary artery disease depends in large part on the presenting clinical syndrome. Patients with stable and unstable angina are treated initially with antiplatelet therapy (aspirin) to reduce the likelihood of clot formation and therefore to reduce the chance of acute MI. Intravenous heparin is also a mainstay of treatment for unstable angina, and works by inhibiting further clot formation. Other, newer anti-platelet agents include several intravenously administered potent inhibitors of platelet aggregation called the 2b,3a inhibitors, which are also reserved for unstable anginal syndromes.

Beta-blockers can be administered orally or intravenously to decrease myocardial oxygen demand by reducing heart rate and contractility and, by reduction of blood pressure, wall tension.

Nitrates are effective in reducing venous return to the heart (pre-load) thereby reducing wall tension. Another effect of organic nitrates is to cause a direct vasodilatation of the coronary arteries, thereby increasing coronary perfusion.

Calcium channel blockers are a relatively large class of agents which act by different mechanisms. Some of them act more through peripheral vasodilatation and reduction of blood pressure, i.e. wall stress, while others act through negative chronotropic effects, thereby reducing heart rate and again reducing oxygen demand. All of them cause some coronary vasodilatation to lesser or greater extents, resulting in increased coronary blood flow.

Thrombolytic therapy remains the most important modality for the treatment of acute myocardial infarction and, in the absence of contra-indications, is recommended for all patients presenting within the first several hours of myocardial infarction. Thrombolytic therapy is usually combined with longer-acting anti-coagulants including heparin and anti-platelet agents. In addition, intravenous nitroglycerin and often ß-blockers are added to the regimen for acute myocardial infarction.

Nonmedical modalities will be discussed briefly and include:

1) Percutaneous transluminal coronary angioplasty (PTCA)

2) Directional coronary atherectomy (DCA)

3) Coronary artery bypass grafting (CABG)

 These modalities are usually reserved for those patients who are refractory to conventional medical therapy. Most of these patients continue to have frequent angina, rest angina, prolonged angina, or post-infarction angina. PTCA and DCA are usually reserved for patients with one-vessel and sometimes two-vessel coronary artery disease, while CABG is often recommended for patients with triple-vessel coronary artery disease or disease of the left main coronary artery. Optimum benefit is obtained from CABG in patients who have three-vessel coronary artery disease and impairment of left ventricular systolic function.